Hypertension is a common cardiovascular disease. In the United States, more than 30% of adults develop hypertension. The disease is a well-known risk factor for major cardiovascular diseases such as myocardial infarction, heart failure, renal failure, and stroke. In most patients with hypertension, the underlying cause remains unknown, indicating that additional contributing factors remain to be discovered. To date, genetic mutations that impair sodium homeostasis have been reported in some hypertensive patients. These findings are consistent with the notion that hypertension reflects inadequate control of salt and body fluid balance.
Atrial natriuretic peptide (ANP) is a key hormone for sodium homeostasis and normal blood pressure. Mutations that alter ANP amino acids have been found in hypertensive patients. In heart cells, ANP is produced as a precursor, pro-ANP, which is activated to ANP by corin, a membrane-bound serine protease. Yan et al., Proc Natl Acad Sci U.S.A 97, 8525-8529 (2000). This function of corin is important for maintaining normal blood pressure. As a trypsin-like enzyme, corin is made as an inactive zymogen, which is activated by proteolytic cleavage at a conserved site, Arg-801↓Ile-802 (FIG. 2a). Yan et al., J Biol Chem 274, 14926-14935 (1999). CORIN gene variants and mutations preventing corin activation have been identified in patients with hypertension and pre-eclampsia. This zymogen activation step is critical for corin activity. For many years, however, the enzyme responsible for corin activation remained unidentified.